Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.     

Anti-DFS70 antibodies in 597 healthy hospital workers

OBJECTIVE: Autoantibodies against DFS70 (dense fine speckles 70) antigen (also known as lens epithelium-derived growth factor) have been recently identified among the antinuclear antibodies (ANAs) in patients with atopic disorders. We undertook this study to examine the frequency of anti-DFS70 antibodies in a large number of healthy people. METHODS: Sera of 597 healthy individuals working in a hospital (142 men, 455 women) were analyzed for ANAs and for anti-DFS70 antibodies by indirect immunofluorescence (IIF) with HEp-2 cells as a substrate and by immunoblotting using DFS70 recombinant protein and whole HeLa cell extract. RESULTS: ANAs were present in 20% of all individuals by IIF. Nine percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80, 5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti-DFS70 antibody-positive individuals. Surprisingly, this was 11% of the whole population and 54% of the ANA-positive population. The percentage of female anti-DFS70 antibody-positive subjects (86%; 55 of 64 subjects) was higher than the percentage of female anti-DFS70 antibody-negative subjects (75%; 398 of 533 subjects) (P < 0.05). The prevalence of anti-DFS70 antibody-positive sera decreased with increasing age (P = 0.0017). CONCLUSION: Considering that anti-DFS70 antibody positivity is rare in patients with systemic autoimmune diseases, introducing the anti-DFS70 antibody examination as a screening test for ANA-positive persons could be used to rule out systemic autoimmune diseases, resulting in considerable cost-saving potential. In addition, this test defines a subpopulation of healthy people in whom long-term followup might reveal health-related implications of this finding, since anti-DFS70 antibodies have been shown to be associated with some illnesses.     

Antitumor effect of MCC-465, pegylated liposomal doxorubicin tagged with newly developed monoclonal antibody GAH, in colorectal cancer xenografts

MCC-465 is an immunoliposome-encapsulated doxorubicin. The liposome is tagged with polyethylene glycol and the F(ab')2 of a monoclonal antibody named GAH, a human antibody obtained by the hybridoma technique. The epitope recognized by GAH is not well characterized, but human gastric, colorectal, and mammary cancer cells were GAH-positive, while the normal counterparts were GAH-negative. Pegylated liposome doxorubicin (PLD) and MCC-465 did not show significant antitumor activity against GAH-negative Caco-2 xenografts. On the other hand, MCC-465 exhibited significantly superior antitumor effects against GAH-positive WiDr-Tc and SW837 xenografts, compared with PLD. Immunohistochemistry with GAH revealed that 94% (100 of 106) of surgical specimens of colorectal cancer were GAH-positive. These results warrant a phase I clinical trial of MCC-465 for patients with metastatic colorectal cancer.     

Resected cases with primary lung cancer after preoperative high dose irradiation

After greater than 60 gray (Gy) irradiation, we performed the pulmonary resection in the 18 primary lung cancer cases. The mean irradiation dose to the tumor was 68.2 (range 60-101) Gy, and the mean irradiation dose to the bronchial stump was 47.1 (range 0-82) Gy. Median time from end of irradiation to surgical resection was 136 (range 20-894) days. One partial resection, 9 single lobectomies, 3 double lobectomies, and 5 pneumonectomies were done. Mainly, we closed the bronchial stump by the automatic stapling device and additional hand suturing. The bronchial stump was covered in the 12 cases by the owner stalk thymus, the intercostals muscular flap, the omentum flap, and et al. The major postoperative complications due to preoperative irradiation were not seen. Bronchopleural fistulas did not occur. Pathologically, the wall of the submucosal capillary vessels were getting thick in the patients operated more than 3 months later after irradiation. In such cases with the decrease of the blood flow, the bronchial stump should be covered. The pulmonary resection after the high dose irradiation was considered to be tolerable.     

Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.     

Functional outcome,rehabilitation use and length of hospital stay for stroke patients in south Madrid

BACKGROUND: Health status and use of resources by stroke patients in Spain are unknown. METHODS: A total of 103 acute stroke patients resident in south Madrid, population 665,168, were seen in 1996 at a general hospital and three primary care centres and evaluated at 5-10 days, 3 and 6 months after stroke. Health outcomes and patterns of rehabilitation and hospital use by patient groups were studied using multivariate logistic regression. RESULTS: The group receiving rehabilitation exhibited higher levels of impairment, disability and handicap at each time point, these differences decreasing with time, except in the distribution of walking ability which was unimodal in that group. Younger age, poor walking ability and motor capacity, pain on the paretic side and living with a spouse predicted use of rehabilitation; low level of education predicted a long hospital stay. CONCLUSION: Rehabilitation for stroke in south Madrid was sparse and used mainly by young, severely affected patients.     

Acute effects of passive smoking on the coronary circulation in healthy young adults

CONTEXT: Recent studies have shown that passive smoking is a risk factor for ischemic heart disease and may be associated with vascular endothelial dysfunction. The acute effects of passive smoking on coronary circulation in nonsmokers are not known. OBJECTIVE: To determine the acute effects of passive smoking on coronary circulation using coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study conducted from September 2000 to November 2000 among 30 Japanese men (mean age, 27 years; 15 healthy nonsmokers and 15 asymptomatic active smokers) without history of hypertension, diabetes mellitus, or hyperlipidemia. MAIN OUTCOME MEASURES: Coronary flow velocity reserve, calculated as the ratio of hyperemic to basal coronary flow velocity induced by intravenous infusion of adenosine triphosphate and measured in each participant before and after a 30-minute exposure to environmental tobacco smoke. RESULTS: Heart rate and blood pressure responses to adenosine triphosphate infusion were not affected by passive smoking exposure in either group. Passive smoking exposure had no effect on basal coronary flow velocity in either group. Mean (SD) CFVR in nonsmokers was significantly higher than that in active smokers before passive smoking exposure (4.4 [0.91] vs 3.6 [0.88], respectively; P =.02), while CFVR after passive smoking exposure did not differ between groups (P =.83). Passive smoking exposure significantly reduced mean (SD) CFVR in nonsmokers (4.4 [0.91] vs 3.4 [0.73], respectively; P<.001). CONCLUSIONS: Passive smoking substantially reduced CFVR in healthy nonsmokers. This finding provides direct evidence that passive smoking may cause endothelial dysfunction of the coronary circulation in nonsmokers.